Fluorinated cbd compounds, compositions and uses thereof

ABSTRACT

The present invention relates to fluorine substituted CBD compounds, compositions thereof and uses thereof for the preparation of medicaments.

TECHNOLOGICAL FIELD

The present invention relates to fluorine substituted CBD compounds,compositions thereof and uses thereof for the preparation ofmedicaments.

PRIOR ART

References considered to be relevant as background to the presentlydisclosed subject matter are listed below:

REFERENCES

-   -   Campos A C, Guimarães F S. Involvement of 5HT1A receptors in the        anxiolytic-like effects of cannabidiol injected into the        dorsolateral periaqueductal gray of rats. Psychopharmacology        (Burl). 199(2):223-30, 2008.    -   File S E. Behavioural detection of anxiolytic action, in        Experimental approaches to anxiety and depression (Elliott J M,        Heal D J and Marsden C A eds) pp 25-44, Wiley, New York, 1992.    -   Issy A C, Salum C, Del Bel E A. Nitric oxide modulation of        methylphenidate-induced disruption of prepulse inhibition in        Swiss mice. Behav Brain Res. 205(2):475-81, 2009.    -   Long L E, Malone D T, Taylor D A. Cannabidiol Reverses        MK-801-Induced Disruption of Prepulse Inhibition in Mice.        Neuropsychopharmacology 31:795-803, 2006.    -   Moreira F A, Guimarães F S. Cannabidiol inhibits the        hyperlocomotion induced by psychotomimetic drugs in mice. Eur J        Pharmacol. 512(2-3):199-205, 2005.    -   Onaivi E S, Green M R, Martin B R. Pharmacological        characterization of cannabinoids in the levated plus maze J        Pharmacol Exp Ther 255:1002-9, 1990.    -   Paxinos G. and Watson C. The rat brain in stereotaxic        coordinates. Academic Press, New York, 1997.    -   Zanelati T V, Biojone C, Moreira F A, Guimarães F S, Joca S R.        Antidepressant-like effects of cannabidiol in mice: possible        involvement of 5-HT1A receptors. Br J Pharmacol.159:122-8, 2010.

Acknowledgement of the above references herein is not to be inferred asmeaning that these are in any way relevant to the patentability of thepresently disclosed subject matter.

GENERAL DESCRIPTION

The present invention provides a compound having the general formula(I):

wherein

is a single or double bond;

R₁ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, —C(═O)R₈,—C(═O)OR₉ each optionally substituted by at least one F;

R₂ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, eachoptionally substituted by at least one F;

R₃ and R₄ are each independently selected from H, straight or branchedC₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one ofR₃ and R₄ is different than H;

R₅ is selected from a straight or branched C₆-C₁₂ alkyl, a straight orbranched C₅-C₉ alkoxy, a straight or branched C₁-C₇ ether, each beingoptionally substituted by at least one substituent selected from —OH,—NH₃, straight or branched C₁-C₅ amine, halogen, phenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl;

R₈, and R₉ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; and

R₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₃, R₁₄, R₁₅ and R₁₆ are each optionally selected from H and F;

provided that at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F or at least oneof R₁ and R₂ is substituted with F.

In another one of its aspects the invention provides a compound havingthe general formula (II):

wherein

is a single or double bond;

R₁ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, —C(═O)R₈,—C(═O)OR₉ each optionally substituted by at least one F;

R₃ and R₄ are each independently selected from H, straight or branchedC₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one ofR₃ and R₄ is different than H;

R₅ is selected from a straight or branched C₆-C₁₂ alkyl, a straight orbranched C₅-C₉ alkoxy, a straight or branched C₁-C₇ ether, each beingoptionally substituted by at least one substituent selected from —OH,—NH₃, straight or branched C₁-C₅ amine, halogen, phenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl;

R₈, and R₉ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; and

R₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are each optionally selected from H and F;

provided that at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F or R₁ issubstituted with F.

In another one of its aspects the invention provides a compound havingthe general formula (III):

wherein

is a single or double bond;

R₁ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, —C(═O)R₈,—C(═O)OR₉;

R₂ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl;

R₃ and R₄ are each independently selected from H, straight or branchedC₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one ofR₃ and R₄ is different than H;

R₅ is selected from a straight or branched C₆-C₁₂ alkyl, a straight orbranched C₅-C₉ alkoxy, a straight or branched C₁-C₇ ether, each beingoptionally substituted by at least one substituent selected from —OH,—NH₃, straight or branched C₁-C₅ amine, halogen, phenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl;

R₈, and R₉ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; and

R₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₃ and R₁₄ are each optionally selected from H and F; provided that atleast one of R₁₃ and R₁₄ are F.

In yet a further aspect the invention provides a compound of generalformula (IV)

wherein

is a single or double bond;

R₁ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, —C(═O)R₈,—C(═O)OR₉ each optionally substituted by at least one F;

R₂ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, eachoptionally substituted by at least one F;

R₃ and R₄ are each independently selected from H, straight or branchedC₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one ofR₃ and R₄ is different than H;

R₅ is selected from a straight or branched C₆-C₁₂ alkyl, a straight orbranched C₅-C₉ alkoxy, a straight or branched C₁-C₇ ether, each beingoptionally substituted by at least one substituent selected from —OH,—NH₃, straight or branched C₁-C₅ amine, halogen, phenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl;

R₈, and R₉ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; and

R₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine;

R₁₅ and R₁₆ are each optionally selected from H and F;

provided that at least one of R₁₅ and R₁₆ is F or at least one of R₁ andR₂ is substituted with F.

In some embodiments

is a double bond.

In some other embodiments R₁ straight or branched C₁-C₈ alkyl; R₃ and R₄are each independently —OR₁₀; R₁₀ is selected from H, a straight orbranched C₁-C₅ alkyl.

In further embodiments R₁ is straight or branched C₁-C₈ alkyl, and R₃and R₄ are OH.

In other embodiments, R₃ and R₄ are each independently selected from H,—OR₁₀, and —OC(═O)R₁₂; R₁₀ is selected from H, a straight or branchedC₁-C₅ alkyl; and R₁₂ is selected from H, OH, straight or branched C₁-C₅alkyl, —NH₃, straight or branched C₁-C₅ amine.

In some embodiments, R₅ is a straight or branched C₆-C₁₂ alkyl.

In further embodiments of a compound of the invention at least one ofR₁₃, R₁₄, R₁₅ and R₁₆ is F.

In other embodiments of a compound of the invention at least one of R₁₃and R₁₄ is F.

In further embodiments of a compound of the invention at least one ofR₁₅ and R₁₆ is F.

In other embodiments of a compound of the invention at least one of R₁and R₂ is substituted with F.

In yet further embodiments of a compound of the invention R₁ is selectedfrom straight or branched C₁-C₈ alkyl, straight or branched C₂-C₁₀alkenyl, straight or branched C₂-C₁₀ alkynyl, each being substituted byF.

In further embodiments of a compound of the invention R₂ is selectedfrom straight or branched C₁-C₈ alkyl, straight or branched C₂-C₁₀alkenyl, straight or branched C₂-C₁₀ alkynyl, each substituted by F.

In further embodiments a compound of the invention is of the generalformula (V):

wherein R₁, R₂, R₃, R₄ and R₅ are as defined therein.

In other embodiments a compound of the invention is of the generalformula (VI):

wherein R₁, R₃, R₄, R₅, R₁₅ and R₁₆ are as defined therein.

The present invention provides a compound having the general formula(I):

wherein

is a double bond;

R₁ is a straight or branched C₁-C₈ alkyl optionally substituted by atleast one F;

R₂ is a straight or branched C₂-C₁₀ alkenyl optionally substituted by atleast one F;

R₃ and R₄ are each independently selected from H, —OR₁₀, —OC(═O)R₁₂;provided that at least one of R₃ and R₄ is different than H;

R₅ is a straight or branched C₆-C₁₂ alkyl optionally substituted by atleast one substituent selected from —OH, —NH₃, straight or branchedC₁-C₅ amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl;

R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; and

R₁₂ is selected from H, OH, straight or branched C₁-C₅ alkyl, straightor branched C₁-C₅ alkoxy, —NH₃, straight or branched C₁-C₅ amine;

R₁₃, R₁₄, R₁₅ and R₁₆ are each optionally selected from H and F;

provided that at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F or at least oneof R₁ and R₂ is substituted with F.

The invention further provides a compound having the formula:

The invention further provides a compound having the formula:

The invention further provides a compound having the formula:

The invention further provides a compound having the formula:

The term “straight or branched C₁-C₈ alkyl” should be understood toencompass a straight or branched hydrocarbon chain having 1, 2, 3, 4, 5,6, 7 or 8 carbon atoms, wherein all bonds are single bonds.

The term “straight or branched C₂-C₁₀ alkenyl” should be understood toencompass a straight or branched hydrocarbon chain having 2, 3, 4, 5, 6,7, 8, 9 or 10 carbon atoms, having at least one double unsaturated bondbetween at least two carbon atoms.

The term “straight or branched C₂-C₁₀ alkynyl” should be understood toencompass a straight or branched hydrocarbon chain having 2, 3, 4, 5, 6,7, 8, 9 or 10 carbon atoms, having at least one triple unsaturated bondbetween at least two carbon atoms.

The term “each optionally substituted by at least one F” should beunderstood to relate to the option of having at least one fluor atomsubstituted on any of the substituents such as R₁ and/or R₂ at anyposition, replacing at least one hydrogen atom.

The term “straight or branched C₅-C₉ alkoxy” should be understood toencompass a radical of —OR wherein R is a straight or branched alkylhaving 5, 6, 7, 8 or 9 carbon atoms.

The term “straight or branched C₁-C₇ ether” should be understood tencompass a radical of —R′OR wherein R is a straight or branched alkylhaving 1, 2, 3, 4, 5, 6 or 7, carbon atoms and R′ is a straight orbranched alkanyl having 1, 2, 3, 4, 5, 6 or 7, carbon atoms.

The term “straight or branched C₁-C₅ amine” should be understood toencompass a primary (—NH₂R), secondary (—NHRR′) or tertiaty amine(—N⁺RR′R″) wherein R, R′ and R″ are each independently a straight orbranched alkyl having 1, 2, 3, 4 or 5 carbon atoms.

The term “halogen” should be understood to encompass any halogen atomsincluding F, Cl, Br and I.

The term “aryl” is meant to encompass an aromatic monocyclic ormulticyclic groups containing from 6 to 19 carbon atoms. Aryl groupsinclude, but are not limited to groups such as unsubstituted orsubstituted fluorenyl, unsubstituted or substituted phenyl, andunsubstituted or substituted naphthyl.

The term “heteroaryl” refers to a monocyclic or multicyclic aromaticring system, in certain embodiments, of about 5 to about 15 memberswherein one or more, in some embodiments between 1 to 3, of the atoms inthe ring system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl,

The term “cycloalkyl” refers to a monocyclic or multicyclic non-aromaticring system, in one embodiment of 3 to 10 members, in another embodimentof 4 to 7 members, in further embodiments between 5 to 6 member carbonatoms.

The term “heterocycloalkyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiments between 5to 6 members, wherein one or more, in certain embodiments between 1 to3, of the atoms in the ring system is a heteroatom, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen orsulfur. In embodiments where the heteroatom(s) is(are) nitrogen, thenitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, acyl, guanidine, or the nitrogen maybe quaternary ammonium group where the substituents are selected asabove.

When referring to a compound of the invention wherein at least one ofR₁₃, R₁₄, R₁₅ and R₁₆ is F or at least one of R₁ and R₂ is substitutedwith F, it should be understood to encompass a compound of the inventionwherein either at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F or at leastone of R₁ and R₂ is a substituent as defined herein above wherein atleast one of its hydrogen atoms (at any location on the moiety) issubstituted by an F atom.

In some other embodiments at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F andat least one of R₁ and R₂ is substituted with F. Under this embodimentthe invention encompasses a compound wherein at least one of R₁₃, R₁₄,R₁₅ and R₁₆ is F and at least one of R₁ and R₂ is a substituent asdefined herein above wherein at least one of its hydrogen atoms (at anylocation on the moiety) is substituted by an F atom.

In another one of its aspects the invention provides a compositioncomprising at least one compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention.

In some embodiments of a composition of the invention, said compositionis a pharmaceutical composition.

A pharmaceutical composition of the present invention have potentantioxidant and/or free radical scavenging properties, that prevent orreduce oxidative damage in biological systems, such as occurs inischemic/reperfusion injury, or in chronic neurodegenerative diseasessuch as Alzheimer's disease, HIV dementia, and many other oxidationassociated diseases.

Thus, the invention provides a composition comprising a compound of theinvention (as defined in any aspect and embodiment of a compound of theinvention) being an antioxidant composition.

As used herein, an “antioxidant” is a substance that, when present in amixture containing an oxidizable substrate biological molecule,significantly delays or prevents oxidation of the substrate biologicalmolecule. Antioxidants can act by scavenging biologically importantreactive free radicals or other reactive oxygen species (O₂ ⁻, H₂O₂,.OH, HOCl, ferryl, peroxyl, peroxynitrite, and alkoxyl), or bypreventing their formation, or by catalytically converting the freeradical or other reactive oxygen species to a less reactive species.

Relative antioxidant activity can be measured by cyclic voltametrystudies, where the voltage (x-axis) is an index of relative antioxidantactivity. The voltage at which the first peak occurs is an indication ofthe voltage at which an electron is donated, which in turn is an indexof antioxidant activity.

“Therapeutically effective antioxidant doses” can be determined byvarious methods, including generating an empirical dose-response curve,predicting potency and efficacy of a congener by using quantitativestructure activity relationships (QSAR) methods or molecular modeling,and other methods used in the pharmaceutical sciences. Since oxidativedamage is generally cumulative, there is no minimum threshold level (ordose) with respect to efficacy. However, minimum doses for producing adetectable therapeutic or prophylactic effect for particular diseasestates can be established.

The present invention also relates to pharmaceutical compositionscomprising at least one compound of the subject invention in admixturewith pharmaceutically acceptable auxiliaries, and optionally othertherapeutic agents. The auxiliaries are “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration or administration via an implant. Thecompositions may be prepared by any method well known in the art ofpharmacy.

Such methods include the step of bringing in association compounds usedin the invention or combinations thereof with any auxiliary agent. Theauxiliary agent(s), also named accessory ingredient(s), include thoseconventional in the art, such as carriers, fillers, binders, diluents,disintegrants, lubricants, colorants, flavouring agents, antioxidants,and wetting agents.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets, dragées orcapsules, or as a powder or granules, or as a solution or suspension.The active ingredient may also be presented as a bolus or paste. Thecompositions can further be processed into a suppository or enema forrectal administration.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material,including instructions for the use of the composition for a use ashereinbefore described.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile injection. The compositions may be presented inunit-dose or multi-dose containers, for example sealed vials andampoules, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of sterile liquid carrier, for examplewater, prior to use. For transdermal administration, e.g. gels, patchesor sprays can be contemplated. Compositions or formulations suitable forpulmonary administration e.g. by nasal inhalation include fine dusts ormists which may be generated by means of metered dose pressurizedaerosols, nebulisers or insufflators.

The exact dose and regimen of administration of the composition willnecessarily be dependent upon the therapeutic or nutritional effect tobe achieved and may vary with the particular formula, the route ofadministration, and the age and condition of the individual subject towhom the composition is to be administered.

In another one of its aspects that invention provides a compound of theinvention, as described herein above in all aspects and embodiments of acompound of the invention, for use in the treatment of at least onecondition, disease or disorder selected from the group consisting of:

-   -   psychiatric disorders (none limiting examples include : anxiety        and stress, depression, schizophrenia, panic, withdrawal        symptoms in cannabis and tobacco addiction, reward-facilitating        effect of morphine and cocaine, lowers cannabis and THC effects        such as memory loss, psychotic-like symptoms);    -   inflammation (none limiting examples include: Crohn's disease,        inflammatory bowel disease, colitis, pancreatitis, asthma,        chronic inflammatory and neuropathic pain);    -   oxidative associated diseases, conditions or disorders        (pathological conditions that result at least in part from the        production of or exposure to free radicals, particularly        oxyradicals, or reactive oxygen species. It is evident to those        of skill in the art that most pathological conditions are        multi-factorial, and that assigning or identifying the        predominant causal factors for any particular condition is        frequently difficult. For these reasons, the term “free radical        associated disease” encompasses pathological states that are        recognized as conditions in which free radicals or reactive        oxygen species (ROS) contribute to the pathology of the disease,        or wherein administration of a free radical inhibitor (e.g.        desferroxamine), scavenger (e.g. tocopherol, glutathione) or        catalyst (e.g. superoxide dismutase, catalase) is shown to        produce detectable benefit by decreasing symptoms, increasing        survival, or providing other detectable clinical benefits in        treating or preventing the pathological state. Oxidative        associated diseases include, without limitation, free radical        associated diseases, such as ischemia, ischemic reperfusion        injury, inflammatory diseases, systemic lupus erythematosis,        myocardial ischemia or infarction, cerebrovascular accidents        (such as a thromboembolic or hemorrhagic stroke) that can lead        to ischemia or an infarct in the brain, operative ischemia,        traumatic hemorrhage (for example a hypovolemic stroke that can        lead to CNS hypoxia or anoxia), spinal cord trauma, Down's        syndrome, Crohn's disease, autoimmune diseases (e.g. rheumatoid        arthritis or diabetes), cataract formation, uveitis, emphysema,        gastric ulcers, oxygen toxicity, neoplasia, undesired cellular        apoptosis, radiation sickness, and others. The present invention        is further directed to a compound or composition of the        invention used in the treatment of oxidative associated diseases        of the CNS. In some embodiments, the pharmaceutical composition        of the present invention is used for preventing, arresting, or        treating neurological damage in Parkinson's disease, Alzheimer's        disease and HIV dementia; autoimmune neurodegeneration of the        type that can occur in encephalitis, and hypoxic or anoxic        neuronal damage that can result from apnea, respiratory arrest        or cardiac arrest, and anoxia caused by drowning, brain surgery        or trauma (such as concussion or spinal cord shock)).    -   rheumatoid arthritis;    -   cardiovascular diseases (none limiting examples include: reduces        infarct size and increase blood flow in stroke; reduces        vasoconstriction; lowers vascular damage caused by a high        glucose environment; reduces the vascular hyperpermeability);    -   obesity (none limiting examples include: food consumption;        lowering appetite); metabolic syndrome);    -   diabetes and associated disorders and symptoms (none limiting        examples include: type 1 and type 2, cardiomyopathy and        retinopathy associated with diabetes);    -   emesis and nausea;    -   ischemic/reperfusion injury associated with myocardial;    -   liver or renal diseases;    -   hypoxia/ischemia injury;    -   neuronal damage due to neurological diseases or injury (none        limiting examples include: Parkinson's disease; Huntington's        disease; Alzheimer's disease; cerebral infarction; hepatic        encephalopathy; traumatic brain injury; cerebral ischemia;        spinal cord injury; memory rescuing effects);    -   cancer and resistance to cancer chemotherapy (none limiting        examples include: cancer cell migration (metastasis); inhibits        angiogenesis);    -   epilepsy and convulsions;    -   and any condition or symptom associated therefrom.

In further embodiments, said condition, disease, disorder or symptomassociated with inflammation is selected from rheumatoid arthritis,multiple sclerosis, inflammatory bowel disease, diabetes and anycombinations thereof.

In yet other embodiments, said disease is a psychiatric diseasecondition or disorder or any symptom associated therewith.

In other embodiments, said psychiatric disease condition or disorder orany symptom associated therewith is selected from anxiety, stress,depression, schizophrenia, panic, substance abuse withdrawal symptoms,reward-facilitating effect of addictive substances, memory loss,psychotic-like symptoms associated with the use of substance abuse.

In another one of its aspects the invention provides a compound of theinvention, as described herein above in all aspects and embodiments of acompound of the invention, for use in reduction of oxidative stress.

When referring to “reduction of oxidative stress” it should beunderstood to encompass any qualitative or quantitative reduction in theoxidative stress in a body tissue or cell of a subject treated with acompound or composition of the invention. Oxidative stress ischaracterized by an imbalance between the systemic manifestation ofreactive oxygen species and a biological system's ability to readilydetoxify the reactive intermediates or to repair the resulting damage.Disturbances in the normal redox state of cells can cause toxic effectsthrough the production of peroxides and free radicals that damage allcomponents of the cell, including proteins, lipids, and DNA. Further,some reactive oxidative species act as cellular messengers in redoxsignaling. Thus, oxidative stress can cause disruptions in normalmechanisms of cellular signaling.

Non limiting list of diseases, conditions or disorders associated withoxidative stress in a cell or tissue of a subject include: cancer,Parkinson's disease, Alzheimer's disease, atherosclerosis, heartfailure, myocardial infarction, Schizophrenia, Bipolar disorder, fragileX syndrome, Sickle Cell Disease, lichen planus, vitiligo, autism, andchronic fatigue syndrome.

In a further aspect the invention provides a compound of the invention,as described herein above in all aspects and embodiments of a compoundof the invention, for use in the treatment of any disease, condition ordisorder caused by or associated with oxidative stress.

Oxidative associated diseases include, without limitation, free radicalassociated diseases, such as ischemia, ischemic reperfusion injury,inflammatory diseases, systemic lupus erythematosis, myocardial ischemiaor infarction, cerebrovascular accidents (such as a thromboembolic orhemorrhagic stroke) that can lead to ischemia or an infarct in thebrain, operative ischemia, traumatic hemorrhage (for example ahypovolemic stroke that can lead to CNS hypoxia or anoxia), spinal cordtrauma, Down's syndrome, Crohn's disease, autoimmune diseases (e.g.rheumatoid arthritis or diabetes), cataract formation, uveitis,emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesiredcellular apoptosis, radiation sickness, and others. The presentinvention is believed to be particularly beneficial in the treatment ofoxidative associated diseases of the CNS, because of the ability of thecannabinoids to cross the blood brain barrier and exert theirantioxidant effects in the brain. In some embodiments, thepharmaceutical composition or compound of the present invention is usedfor preventing, arresting, or treating neurological damage inParkinson's disease, Alzheimer's disease and HIV dementia; autoimmuneneurodegeneration of the type that can occur in encephalitis, andhypoxic or anoxic neuronal damage that can result from apnea,respiratory arrest or cardiac arrest, and anoxia caused by drowning,brain surgery or trauma (such as concussion or spinal cord shock).

In some embodiments, said disease, condition or disorder caused orassociated with oxidative stress are selected from the group consistingof cancer, oxidative neurological disorders, free radical associateddiseases, ischemia, ischemic reperfusion injury, inflammatory diseases,systemic lupus erythematosis, myocardial ischemia or infarction,cerebrovascular accidents, operative ischemia, traumatic hemorrhage,spinal cord trauma, Down's syndrome, Crohn's disease, autoimmunediseases, cataract formation, uveitis, emphysema, gastric ulcers, oxygentoxicity, neoplasia, undesired cellular apoptosis, radiation sickness,and any combinations thereof.

In a further aspect the invention provides a compound as defined in allaspects and embodiments of a compound of the invention, for use in thetreatment of oxidative associated diseases, disorder or condition of theCNS.

In another aspect the invention provides a compound as defined in allaspects and embodiments of a compound of the invention, for use inpreventing, arresting, or treating neurological damage in a subjectsuffering from at least one disease, disorder or condition selected fromParkinson's disease, Alzheimer's disease and HIV dementia; autoimmuneneurodegeneration, hypoxic or anoxic neuronal damage, respiratory arrestor cardiac arrest, anoxia caused by drowning and brain surgery ortrauma.

In a further aspect the invention provides a compound as defined in allaspects and embodiments of a compound of the invention, for use in thetreatment of an ischemic or neurodegenerative disease in the centralnervous.

In some embodiments of a compound for use above, said ischemic orneurodegenerative disease is selected from the group consisting of: anischemic infarct, Alzheimer's disease, Parkinson's disease, and humanimmunodeficiency virus dementia, Down's syndrome, and heart disease orany combinations thereof.

In a further aspect the invention encompasses a use of a compound of theinvention, as described herein above in all aspects and embodiments of acompound of the invention, for the manufacture of a medicament (or apharmaceutical composition).

The invention further provides a use of a compound of the invention, asdescribed herein above in all aspects and embodiments of a compound ofthe invention, for the manufacture of a medicament for the treatment ofat least one condition, disease or disorder selected from the groupconsisting of psychiatric disorders, inflammation, oxidation associatedconditions, rheumatoid arthritis, cardiovascular diseases, obesity,diabetes and associated disorders and symptoms, emesis and nausea,ischemic/reperfusion injury associated with myocardial, liver or renaldiseases, hypoxia/ischemia injury, neuronal damage due to neurologicaldiseases or injury, cancer and resistance to cancer chemotherapy,epilepsy and convulsions, and any condition or symptom associatedtherefrom.

In another aspect the invention provides a use of a compound of theinvention, as described herein above in all aspects and embodiments of acompound of the invention, for the manufacture of a medicament forreduction of oxidative stress.

In yet another aspect the invention provides a use of a compound of theinvention, as described herein above in all aspects and embodiments of acompound of the invention, for the manufacture of a medicament for thetreatment of any disease, condition or disorder caused by or associatedwith oxidative stress.

In some embodiments of a use above, said disease, condition or disordercaused or associated with oxidative stress are selected from the groupconsisting of cancer, oxidative neurological disorders, free radicalassociated diseases, ischemia, ischemic reperfusion injury, inflammatorydiseases, systemic lupus erythematosis, myocardial ischemia orinfarction, cerebrovascular accidents, operative ischemia, traumatichemorrhage, spinal cord trauma, Down's syndrome, Crohn's disease,autoimmune diseases, cataract formation, uveitis, emphysema, gastriculcers, oxygen toxicity, neoplasia, undesired cellular apoptosis,radiation sickness, and any combinations thereof.

In a further aspect the invention provides a use of a compound accordingto the invention (as defined in any of the aspects and embodiments of acompound of the invention), for the manufacture of a medicament for thetreatment of oxidative associated disease, disorder or condition of theCNS.

In another aspect the invention provides a use of a compound accordingto the invention (as defined in any of the aspects and embodiments of acompound of the invention), for the manufacture of a medicament forpreventing, arresting, or treating neurological damage in a subjectsuffering from at least one disease, disorder or condition selected fromParkinson's disease, Alzheimer's disease and HIV dementia; autoimmuneneurodegeneration, hypoxic or anoxic neuronal damage, respiratory arrestor cardiac arrest, anoxia caused by drowning and brain surgery or traumaand any combinations thereof.

In a further aspect the invention provides a use of a compound accordingto the invention (as defined in any of the aspects and embodiments of acompound of the invention), for the manufacture of a medicament for thetreatment of an ischemic or neurodegenerative disease in the centralnervous.

In some embodiments of a use above, said ischemic or neurodegenerativedisease is selected from the group consisting of: an ischemic infarct,Alzheimer's disease, Parkinson's disease, and human immunodeficiencyvirus dementia, Down's syndrome, and heart disease or any combinationsthereof.

The invention also provides a method of treating a condition, disease,disorder or symptom associated with inflammation in a subject in needthereof, said method comprising administering to said subject aneffective amount of at least one compound of the invention, as describedherein above in all aspects and embodiments of a compound of theinvention.

The invention further encompasses a method of reduction of oxidativestress in a tissue or an organ of a subject in need thereof, said methodcomprising administering to said subject an effective amount of at leastone compound of the invention, as described herein above in all aspectsand embodiments of a compound of the invention.

According to a further aspect the invention provides a method oftreating any disease, condition or disorder caused by or associated withoxidative stress a subject in need thereof, said method comprisingadministering to said subject an effective amount of at least onecompound of the invention, as described herein above in all aspects andembodiments of a compound of the invention.

In some embodiments of a method above, said disease, condition ordisorder caused by or associated with oxidative stress are selected fromthe group consisting of cancer, oxidative neurological disorders, freeradical associated diseases, ischemia, ischemic reperfusion injury,inflammatory diseases, systemic lupus erythematosis, myocardial ischemiaor infarction, cerebrovascular accidents, operative ischemia, traumatichemorrhage, spinal cord trauma, Down's syndrome, Crohn's disease,autoimmune diseases, cataract formation, uveitis, emphysema, gastriculcers, oxygen toxicity, neoplasia, undesired cellular apoptosis,radiation sickness, and others.

In a further aspect the invention provides a method for the treatment ofoxidative associated disease, disorder or condition of the CNS in asubject, comprising administering to said subject a therapeuticallyeffective amount of a compound of the invention (as defined in any ofthe aspects and embodiments of a compound of the invention).

In another aspect the invention provides a method for preventing,arresting, or treating neurological damage in a subject suffering fromat least one disease, disorder or condition selected from Parkinson'sdisease, Alzheimer's disease and HIV dementia; autoimmuneneurodegeneration, hypoxic or anoxic neuronal damage, respiratory arrestor cardiac arrest, anoxia caused by drowning and brain surgery ortrauma, comprising administering to said subject a therapeuticallyeffective amount of a compound of the invention (as defined in any ofthe aspects and embodiments of a compound of the invention).

In a further aspect the invention provides a method of treating anischemic or neurodegenerative disease in the central nervous system of asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of the invention (as defined in any ofthe aspects and embodiments of a compound of the invention).

In some embodiments of a method above, said ischemic orneurodegenerative disease is selected from the group consisting of: anischemic infarct, Alzheimer's disease, Parkinson's disease, and humanimmunodeficiency virus dementia, Down's syndrome, and heart disease orany combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosedherein and to exemplify how it may be carried out in practice,embodiments will now be described, by way of non-limiting example only,with reference to the accompanying drawings, in which:

FIG. 1 shows the effects of HU-475 (a compound of the invention 1, 3 and10 nmol, n=8-9 animals/group) and vehicle (n=7) microinjected into thedorsolateral periaqueductal gray of rats submitted to the elevated plusmaze. Data expressed as means±SEM of the percentage of entries onto theopen arms. * indicates significant difference from vehicle (p<0.05).

FIG. 2 shows the effects of HU-475 (a compound of the invention 1, 3 and10 nmol, n=8-9 animals/group) and entries onto vehicle (n=7)microinjected into the dorsolateral periaqueductal gray of ratssubmitted to the elevated plus maze. Data expressed as means±SEM of thepercentage of time spent in the open arms. + indicates a trend (p<0.1)for a difference from vehicle.

FIG. 3 shows the effects of HU-474 (a compound of the invention 1, 3 and10 mg/kg n=6-8 animals/group) and vehicle (n=7) in mice tested in theelevated plus maze. Data expressed as means±SEM of the percentage oftime in the open arms. * indicates significant difference from vehicle.

FIG. 4 shows the effects of HU-474 (a compound of the invention 1, 3 and10 mg/kg n=6-8 animals/group) and vehicle (n=7) in mice tested in theelevated plus maze. Data expressed as means±SEM of the percentage ofentries onto the open arms.

FIG. 5 shows the effects of HU-474 (a compound of the invention 1, 3 and10 mg/kg n=6-8 animals/group) and vehicle (n=7) in mice immobility time(s) showed by mice tested in the FST. Data expressed as means±SEM. *indicates significant difference from vehicle.

FIG. 6 shows the effects of HU-474 (3 and 10 mg/kg i.p.) in mice on theimpairment of PPI induced by MK-801 (M0.5 mg/kg). Results are expressedas means±SEM. * indicates significant difference from vehicle-vehicle, #significant difference from vehicle-MK group.

DETAILED DESCRIPTION OF EMBODIMENTS EXAMPLE 1 Fluorination ofCannabidiol (HU-474)

To a solution of cannabidiol (942 mg, 3 mmol) in dry CH₂Cl₂ (42 mL) wasadded 1-fluoropyridinium triflate (742 mg, 3 mmol) and the reactionmixture was stirred at ambient temperature overnight. After dilutionwith CH₂Cl₂ the mixture was washed with saturated aqueous solution ofNaHCO₃. The organic layer was separated, dried over MgSO₄ andevaporated. The oil obtained was chromatographed on a silica gel column(75 g). Elution with 2% ether in petroleum ether gave the compound4′-fluoro-cannabidiol (HU-474) as a solid (300 mg, 27%) m.p. 59-61° C.¹H NMR (300 MHz, CDCl₃) δ 6.17 (1H, s, arom.) 5.52 (1H, s), 4.56 (1H,s), 4.44 (1H, s), 3.92 (1H, s), 2.50 (2H, b), 2.19-2.05 (2H, b), 1.77(3H, s), 0.86 (3H, t). MS, m/e=332 (M⁺).

EXAMPLE 2 Fluorination of Cannabidiol Diacetate (HU-475)

Step A

To a suspension of SeO₂ (219 mg, 2 mmol) and t-BuOOH (2.8 mL, 70% inwater) in CH₂Cl₂ (7 mL) was added a solution of cannabidiol diacetate (2g, 5 mmol) in CH₂Cl₂ (10 mL). After stirring the mixture at ambienttemperature overnight, it was washed with saturated aqueous solution ofNaHCO₃ followed by a saturated solution of NaHSO₃. The organic layer wasseparated, dried over MgSO₄, filtered and evaporated. The oil obtainedwas purified on a silica gel column (50 g). Elution with 13% ether inpetroleum ether gave the required compound 10-hydroxy-cannabidioldiacetate (670 mg, 40%) as oil. ¹H NMR (300 MHz, CDCl₃), δ 6.7 (2H, s),5.17 (1H, s), 4.99, (1H, s), 4.87 (1H, s), 3.70-3.80 (2H m), 3.53-3.58(1H, m), 2.52-2.57 (2H, t J=7.6 Hz), 2.39-2.48 (1H d J=5.1 Hz), 2.18(6H, s), 2.06 (1H, s), 2.0 (1H, s), 1.58 (1H, s), 1.25-1.31 (4H, m),0.86-0.90 (3H t, J=6.45 Hz).

Step B

The alcohol (414 mg, 1 mmol) in dry CH₂Cl₂ (4 mL) was added under N₂atmosphere to an ice-cold solution of DAST (0.18 mL, 1.5 mmol). After 15min at 0° C. solid Na₂CO₃ (125 mg, 1 mmol) was added. The organic phasewas then washed twice with cold 1 M aqueous Na₂CO₃ solution, followed bywater. The organic layer was separated, dried over MgSO₄, filtered andevaporated. The resulting crude material was purified on a silica gelcolumn (20 g) using 10% ether in petroleum ether to provide thefluorinated product 10-fluoro-cannabidiol diacetate (HU-475) (77.5 mg,18.6%). ¹H NMR (300 MHz, CDCl₃) δ 6.74 (2H, s), 5.21 (1H, s), 5.01 (1H,s), 4.87 (1H, s), 4.60 (1H, s), 4.50 (1H, s), 3.6 (1H, b), 2.73 (1H, t),2.57 (2H, t), 2.21 (6H, s), 2.08-1.59 (8H, ms), 1.32 (3H, s), 0.90 (3H,t). MS, m/e=416 (M⁺).

EXAMPLE 3 In Vivo Effect of HU-474 in Mice and HU-475 in Rats

1. Animals

Male Wistar rats (220-250 g) and Swiss mice (25-30 g) originated fromthe Central Animal Farm of the School of Medicine of Ribeirão Preto(FMRP-USP) were maintained in groups of five animals per box (41×33×17cm) in a temperature controlled room (24±2° C.) with a 12×12 hlight-dark cycle. They received water and food ad libitum throughout thestudy period.

2. Compositions

HU-474 (1, 3 and 10 mg/kg) was administered intraperitoneally (IP) inmice at 10 mL/kg volume and HU-475 (1, 3 and 10 nmol) was injectedintra-dlPAG in rats. Both drugs were dissolved in 2% Tween 80 in sterilesaline.

3. Stereotaxic Surgery (HU-475)

Rats were submitted to a stereotaxic surgery to unilaterally implantcannulae (9.0 mm, 0.6 mm OD) into the dlPAG (coordinates: lateral: −1.9mm; depth: −4.3 mm; angle: 16° from lambda; Paxinos and Watson, 2005),fixed to the skull with acrylic cement (Campos & Guimarães, 2008). Thesurgeries were performed under anesthesia with tribromoethanol 2.5%(10.0 mL/kg, IP) and immediately after the animals received VeterinaryPentabiotic (0.2 mL, intramuscular) and analgesic (Banamine, 1.0 mL/kg,subcutaneous) to prevent infections and decrease post-surgical pain.After surgery, animals underwent a recovery period of 5-7 days beforethe behavioral tests.

4. Microinjection (HU-475)

Animals received unilateral microinjections of vehicle or HU-475 intothe dlPAG before being submitted to the behavioral tests. To this aim,microneedles (10.0 mm, 0 3 mm OD), connected to a microsyringe(Hamilton, USA, 10 mL) through a segment of polyethylene (P10) wereinserted into the guide cannulae. Solutions were injected with the helpof an infusion pump (KD Scientific, USA). A 0.2 μL solution volume wasinjected over 1 min After the injections, the needles remained insertedin the cannulae for additional 30 seconds to prevent drug reflux (Campos& Guimarães, 2008).

5. Apparatus

5.1 Elevated Plus-Maze (EPM) Rats

The wood EPM used to perform the experiments was located in a soundattenuated and temperature controlled room (23° C.), with oneincandescent light (40 W) placed 1.3 m away from the maze. The apparatusconsists of two opposing open arms (50×10 cm) without side walls,perpendicular to two enclosed arms (50×10×40 cm), with a centralplatform common to all arms (10×10 cm). The apparatus is elevated 50 cmabove the ground and has an acrylic edge (1 cm) in the open arms toprevent animal falls. In this model, rodents naturally avoid the openarms, exploring more extensively the enclosed arms. Anxiolytic drugsincrease the exploration in open arms without affecting the number ofenclosed arms entries, which is usually used to assess generalexploratory activity (File, 1992). Ten minutes after the last injectionthe animal was placed on the central platform of the maze with the headfacing one of the enclosed arms. The test lasted for 5 min and wasrecorded. The animal behavior was analyzed with the help of the AnymazeSoftware (version 4.5, Stoelting). This software indicates the locationof the animal in the EPM and automatically calculates the percentage ofentries (Peo) and time spent in the open arms (Pto) and the number ofentries in the enclosed arms (EA). Animals were only considered to enteran open or enclosed arm when 90% of their bodies were inside the region.All experiments were performed in the morning period (8 to 12 a.m.).

5.2 Elevated Plus-Maze (EPM) Mice

Similar to 5.1 except that the each arm measured 30×5 cm.

5.3 Forced Swimming Test (FST) Mice

Animals were individually submitted for 6 min of forced swimming inglass cylinders (height 25 cm, diameter 17 cm) containing 10 cm ofwater. The mice were videotaped and the immobility time (characterizedby slow movements necessary to avoid drowning) was measured during thelast 4-min period. The water was changed after each trial to maintainthe temperature at 23-25° C. and to prevent the influence of alarmsubstances (Zanelati et al., 2010).

6. Histology-Rats

After the behavioral tests animals were anesthetized with chloralhydrate 4% (10 mL/kg) and perfused with saline 0.9%. Brains were removedand kept in formalin solution 10% for 3-7 days. Soon after, brains werecut into 50-μm thick sections in a cryostat (Cryocut 1800). Theinjection sites were identified in diagrams from the Paxinos andWatson's atlas (Paxinos and Watson, 2005). Rats receiving injectionsoutside the aimed area were included in a separate group (out group).

7. Statistical Analysis

Results from HU-475 and HU-474 tests in the elevated plus maze wereanalyzed by Kruskal-Wallis followed by Mann-Whitney tests. Data fromanimals tested in the FST were analyzed by one-way ANOVA followed byDuncan test.

Results.

HU-475. The drug increased the percentage of entries (X²=9.66, DF=4,p<0.05, FIG. 1) and tended to do the same (X²=8.5, DF=4, p=0.075, FIG.2) with the percentage of time spent into the open arms. No effect wasfound in the number of enclosed arm entries.

FIG. 1 shows the effects of HU-475 (1, 3 and 10 nmol, n=8-9animals/group) and vehicle (n=7) microinjected into the dorsolateralperiaqueductal gray of rats submitted to the elevated plus maze. Resultsfrom animals that received the dose of 3 nmol outside the target regionare shown in the OUT group (n=6). Data expressed as means±SEM of thepercentage of entries onto the open arms. * indicates significantdifference from vehicle (p<0.05). FIG. 2 shows the effects of HU-475 (1,3 and 10 nmol, n=8-9 animals/group) and vehicle (n=7) microinjected intothe dorsolateral periaqueductal gray of rats submitted to the elevatedplus maze. Results from animals that received the dose of 3 nmol outsidethe target region are shown in the OUT group. Data expressed asmeans±SEM of the percentage of time spent in the open arms. + indicatesa trend (p<0.1) for a difference from vehicle.

HU-474. The drug increased the percentage of time spent in the open armsof the pEPM (X²=8.13, DF=3, p<0.05, FIG. 3. No effect was found in thepercentage of entries onto these same arms (FIG. 4) and the number ofenclosed arms entries. The drug also decreased immobility time in theFST (F3,2=4.06, p=0.019, FIG. 5) at the dose of 3 m/kg. The doses of 1and 10 mg/kg were ineffective. FIG. 3 shows the effects of HU-474 (1, 3and 10 mg/kg n=6-8 animals/group) and vehicle (n=7) in mice tested inthe elevated plus maze. Data expressed as means±SEM of the percentage oftime in the open arms. * indicates significant difference from vehicle.FIG. 4 shows the effects of HU-474 (1, 3 and 10 mg/kg n=6-8animals/group) and vehicle (n=7) in mice tested in the elevated plusmaze. Data expressed as means±SEM of the percentage of entries onto theopen arms. FIG. 5 shows the effects of HU-474 (1, 3 and 10 mg/kg n=6-8animals/group) and vehicle (n=7) in mice immobility time (s) showed bymice tested in the FST. Data expressed as means±SEM. * indicatessignificant difference from vehicle.

Discussion (Comparative Results with CBD)

Intra-dlPAG injection of HU-475 increased exploration of the open armsof the EPM without changing the number of enclosed arm entries. Thisindicates an anxiolytic-like effect (File, 1991) and was similar to thatproduced by CBD using the same paradigm, including a bell-shapeddose-response curve. However, the effective dose of CBD was 30 nmol(doses tested: 15, 30 and 60 nmol), same dose produced ananxiolytic-like effect in the Vogel punished licking test (Campos &Guimarães, 2008). In this model, therefore, HU-475 was 10 times morepotent that CBD.

Systemic administration of HU-474 induced anxiolytic-like effects inmice tested the EPM with a characteristic bell-shaped dose-responsecurve. The effective dose was 3 mg/kg. In comparison with CBD, Onaivi etal. (1990) in a study conducted with a different mice strain (ICR),observed similar anxiolytic effects at the doses of 1 and 10 mg/kg i.p.(with the 10 mg/kg of CBD being more effective). HU-474 also decreaseimmobility time in mice tested in the forced swimming test, a modelsensitive to antidepressant drugs. CBD also produced anantidepressant-like effect in Swiss mice tested in this model at thedose of 30 mg/kg i.p. (doses tested 3, 10, 30 and 100 mg/kg). Therefore,in this model HU-474 was 10 times more potent than CBD.

EXAMPLE 4 Pre-Pulse Inhibition Test (HU-474)

1. Animals

The experiments were performed using male C57BL/6J mice weighting 25-30g. The animals were maintained throughout the experimental period understandard laboratory conditions with free access to water and food willbe used.

2. Compositions

HU-474 (3 and 10 mg/kg) was dissolved in 2% Tween 80 in sterile saline(vehicle). MK-801 (a NMDA antagonist, 0.5 mg/kg, Sigma, USA) wasdissolved in saline. Drugs were administered intraperitoneally (ip) at10 mL/kg volume.

3. Experimental Procedure

The animals (n=9-11/group) received i.p. administration of vehicle orHU-474 (3 and 10 mg/kg) followed, 30 minutes later, by saline or MK-801(0.5 mg/kg), resulting in the following experimental groups:vehicle+saline, HU 10+saline, vehicle+MK-801, HU 3+MK-801, HU 10+MK-801.The animals were submitted to PPI test 20 minutes after the last druginjection.

4. Pre-Pulse Inhibition (PPI)

The PPI was carried out in three consecutive steps. The first consistedof an acclimation period during which no stimulus was presented. In thesecond step, called habituation, only the stimulus that triggers thestartle (pulse) was presented. The step that assessed the inhibition ofstartle response pulse consisted of 64 random presentations of thedifferent stimuli: (i) pulse (white noise) 105 dB at 20 ms, (II)pre-pulse (pure tone frequency of 7 kHz) 80, 85 and 90 dB at 10 ms,(III) followed by pre-pulse 100 ms interval between them and (IV) zero(no stimulus). During this session the stimuli are presented at regularintervals of 30 s, 8 presentations of each stimulus. The percentage ofthe PPI was expressed as the percent inhibition of startle amplitude inresponse to multiple presentations of the pulse preceded by pre-pulse(PP), depending on the amplitude of the response only to the pulse (P),which was obtained in the following formula: % PPI=100−((PP/P)×100).Using this formula 0% represents no difference between the amplitude ofstartle triggered only by the pulse or pulse preceded by the pre-pulseand therefore no pre-pulse inhibition. This transformation was performedin order to reduce the statistical variability attributable todifferences between animals and represents a direct measure of pre-pulseinhibition (Issy et al., 2009).

5 Statistical Analysis

The percentage of PPI was analyzed by repeated measures MANOVA with thetreatment as the independent factor and the prepulse intensity (80, 85and 90 dB) as repeated measure. Duncan's post hoc test (P<0.05) was usedto identify differences revealed by significant MANOVA.

Results

The MANOVA revealed significant main effects of prepulse intensity(F_(2,70)=23.53, P<0.05) and treatment (F_(4,35)=45.42, P<0.05) but nointeraction between prepulse intensity and treatment (F8,70=1.08,P>0.05). MK-801 promoted significant PPI disruption for all prepulseintensities tested (P<0.05, Duncan post-test). HU-474 (10 mg/kg)attenuated MK-801 PPI disruption in all prepulse intensities tested(P<0.05, FIG. 6). FIG. 6 shows the effects of HU-474 (3 and 10 mg/kgi.p.) in mice on the impairment of PPI induced by MK-801 (M0.5 mg/kg).Results show the percent inhibition of startle amplitude in response tomultiple presentations of the pulse preceded by pre-pulse and areexpressed as means±SEM. * indicates significant difference fromvehicle-vehicle, # significant difference from vehicle-MK group.

Discussion (Comparison with CBD results)

A single CBD administration (5 mg/kg, I.p.) attenuated PPI deficitscaused by MK801 (0.3-1 mg/kg, i.p.) in Swiss mice (Long et al., 2006).Observe that in this case the effective CBD dose (the authors alsotested 1 and 15 mg/kg) was lower than that observed in HU-474 (10mg/kg).

The above experimental procedure is also performed with 30 mg/kg dose ofHU-474. HU-474 is also tested in dopamine-based models (hyperlocomotioninduced by d-amphetamine). CBD effective doses are 30 and 60 mg/kg(Swiss mice). 30mg/kg dose are able to attenuate the hyper-locomotioninduced by MK801 (Moreira and Guimarães, 2005).

1-48. (canceled)
 49. A compound having the general formula (I):

wherein

is a single or double bond; R₁ is selected from straight or branchedC₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl, straight or branchedC₂-C₁₀ alkynyl, —C(═O)R₈, —C(═O)OR₉ each optionally substituted by atleast one F; R₂ is selected from straight or branched C₁-C₈ alkyl,straight or branched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀alkynyl, each optionally substituted by at least one F; R₃ and R₄ areeach independently selected from H, straight or branched C₁-C₅ alkyl,—OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one of R₃ and R₄ isdifferent than H; R₅ is selected from a straight or branched C₆-C₁₂alkyl, a straight or branched C₅-C₉ alkoxy, a straight or branched C₁-C₇ether, each being optionally substituted by at least one substituentselected from —OH, —NH₃, straight or branched C₁-C₅ amine, halogen,phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R₈, and R₉are independently selected from H, OH, straight or branched C₁-C₅ alkyl,straight or branched C₁-C₅alkoxy, —NH₃, straight or branched C₁-C₅amine; R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; andR₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine; R₁₃, R₁₄, R₁₅ and R₁₆ are each optionally selectedfrom H and F; provided that at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is For at least one of R₁ and R₂ is substituted with F.
 50. A compoundaccording to claim 49, having the general formula (II):

wherein

is a single or double bond; R₁ is selected from straight or branchedC₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl, straight or branchedC₂-C₁₀ alkynyl, —C(═O)R₈, —C(═O)OR₉ each optionally substituted by atleast one F; R₃ and R₄ are each independently selected from H, straightor branched C₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that atleast one of R₃ and R₄ is different than H; R₅ is selected from astraight or branched C₆-C₁₂ alkyl, a straight or branched C₅-C₉ alkoxy,a straight or branched C₁-C₇ ether, each being optionally substituted byat least one substituent selected from —OH, —NH₃, straight or branchedC₁-C₅ amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl; R₈, and R₉ are independently selected from H, OH,straight or branched C₁-C₅ alkyl, straight or branched C₁-C₅alkoxy,—NH₃, straight or branched C₁-C₅ amine; R₁₀ is selected from H, astraight or branched C₁-C₅ alkyl; and R₁₁ and R₁₂ are independentlyselected from H, OH, straight or branched C₁-C₅ alkyl, straight orbranched C₁-C₅ alkoxy, —NH₃, straight or branched C₁-C₅ amine; R₁₃, R₁₄,R₁₅, R₁₆ and R₁₇ are each optionally selected from H and F; providedthat at least one of R₁₃, R₁₄, R₁₅ and R₁₆ is F or R₁ is substitutedwith F.
 51. A compound according to claim 49, having the general formula(III):

wherein

is a single or double bond; R₁ is selected from straight or branchedC₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl, straight or branchedC₂-C₁₀ alkynyl, —C(═O)R₈, —C(═O)OR₉; R₂ is selected from straight orbranched C₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl, straight orbranched C₂-C₁₀ alkynyl; R₃ and R₄ are each independently selected fromH, straight or branched C₁-C₅ alkyl, —OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂;provided that at least one of R₃ and R₄ is different than H; R₅ isselected from a straight or branched C₆-C₁₂ alkyl, a straight orbranched C₅-C₉ alkoxy, a straight or branched C₁-C₇ ether, each beingoptionally substituted by at least one substituent selected from —OH,—NH₃, straight or branched C₁-C₅ amine, halogen, phenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl; R₈, and R₉ areindependently selected from H, OH, straight or branched C₁-C₅ alkyl,straight or branched C₁-C₅alkoxy, —NH₃, straight or branched C₁-C₅amine; R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; andR₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine; R₁₃ and R₁₄ are each optionally selected from Hand F; provided that at least one of R₁₃ and R₁₄ are F.
 52. A compoundaccording to claim 49, of general formula (IV)

wherein

is a single or double bond; R₁ is selected from straight or branchedC₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl, straight or branchedC₂-C₁₀ alkynyl, —C(═O)R₈, —C(═O)OR₉ each optionally substituted by atleast one F; R₂ is selected from straight or branched C₁-C₈ alkyl,straight or branched C₂-C₁₀ alkenyl, straight or branched C₂-C₁₀alkynyl, each optionally substituted by at least one F; R₃ and R₄ areeach independently selected from H, straight or branched C₁-C₅ alkyl,—OR₁₀, —C(═O)R₁₁, —OC(═O)R₁₂; provided that at least one of R₃ and R₄ isdifferent than H; R₅ is selected from a straight or branched C₆-C₁₂alkyl, a straight or branched C₅-C₉ alkoxy, a straight or branched C₁-C₇ether, each being optionally substituted by at least one substituentselected from —OH, —NH₃, straight or branched C₁-C₅ amine, halogen,phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R₈, and R₉are independently selected from H, OH, straight or branched C₁-C₅ alkyl,straight or branched C₁-C₅alkoxy, —NH₃, straight or branched C₁-C₅amine; R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl; andR₁₁ and R₁₂ are independently selected from H, OH, straight or branchedC₁-C₅ alkyl, straight or branched C₁-C₅ alkoxy, —NH₃, straight orbranched C₁-C₅ amine; R₁₅ and R₁₆ are each optionally selected from Hand F; provided that at least one of R₁₅ and R₁₆ is F or at least one ofR₁ and R₂ is substituted with F.
 53. A compound according to claim 49,wherein

is a double bond.
 54. A compound according to claim 49, wherein R₁straight or branched C₁-C₈ alkyl; R₃ and R₄ are each independently—OR₁₀; R₁₀ is selected from H, a straight or branched C₁-C₅ alkyl.
 55. Acompound according to claim 49, wherein R₁ is straight or branched C₁-C₈alkyl, and R₃ and R₄ are OH.
 56. A compound according to claim 49,wherein R₅ is a straight or branched C₆-C₁₂ alkyl.
 57. A compoundaccording to claim 49, wherein at least one of R₁₃, R₁₄, R₁₅ and R₁₆ isF. A compound according to claim 1, wherein at least one of R₁ and R₂ issubstituted with F.
 58. A compound according to claim 49, wherein R₁ isselected from straight or branched C₁-C₈ alkyl, straight or branchedC₂-C₁₀ alkenyl, straight or branched C₂-C₁₀ alkynyl, each substituted byF.
 59. A compound according to claim 49, wherein R₂ is selected fromstraight or branched C₁-C₈ alkyl, straight or branched C₂-C₁₀ alkenyl,straight or branched C₂-C₁₀ alkynyl, each substituted by F.
 60. Acompound according to claim 49, having the general formula (V):

wherein R₁, R₂, R₃, R₄ and R₅ are as defined therein.
 62. A compoundaccording to claim 49, having the general formula (VI):

wherein R₁, R₃, R₄, R₅, R₁₅ and R₁₆ are as defined therein.
 63. Acomposition comprising at least one compound according to claim
 49. 64.A method of treating a condition, disease, disorder or symptomassociated with at least one of inflammation, oxidative stress,oxidative associated disease, disorder or condition of the CNS, ischemicor neurodegenerative disease in the CNS in a subject in need thereof,said method comprising administering to said subject an effective amountof at least one compound according to claim
 49. 65. A method accordingto claim 64, wherein said disease, condition or disorder caused by orassociated with oxidative stress are selected from the group consistingof cancer, oxidative neurological disorders, free radical associateddiseases, ischemia, ischemic reperfusion injury, inflammatory diseases,systemic lupus erythematosis, myocardial ischemia or infarction,cerebrovascular accidents, operative ischemia, traumatic hemorrhage,spinal cord trauma, Down's syndrome, Crohn's disease, autoimmunediseases, cataract formation, uveitis, emphysema, gastric ulcers, oxygentoxicity, neoplasia, undesired cellular apoptosis, radiation sickness,and any combinations thereof.
 66. A method according to claim 65,wherein the ischemic or neurodegenerative disease is selected from thegroup consisting of: an ischemic infarct, Alzheimer's disease,Parkinson's disease, and human immunodeficiency virus dementia, Down'ssyndrome, and heart disease or any combinations thereof.
 67. A methodfor preventing, arresting, or treating neurological damage in a subjectsuffering from at least one disease, disorder or condition selected fromParkinson's disease, Alzheimer's disease and HIV dementia; autoimmuneneurodegeneration, hypoxic or anoxic neuronal damage, respiratory arrestor cardiac arrest, anoxia caused by drowning and brain surgery or traumaand any combinations thereof, comprising administering to said subject atherapeutically effective amount of a compound of claim 49.